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Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia (RNA-Seq II)

ABSTRACT: Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-Luc+ AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitors (TP-0903, 60 mg/kg, once daily for 5 days/week; gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 7 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and RNA-seq was performed on total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the transcriptional changes induced by TP-0903 or gilteritinib in MOLM13 AML xenograft model.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180181 | GEO | 2021/07/22

REPOSITORIES: GEO

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Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia (RNA-Seq I)

Project description:Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-RES-Luc+ (MOLM13 cells with a D835Y mutation generating a resistant phenotype) AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitors (TP-0903, 60 mg/kg, once daily for 5 days/week; gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 13 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and RNA-seq was performed on total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the transcriptional changes induced by TP-0903 or gilteritinib in MOLM13-RES AML xenograft model.

2021-07-22 | GSE180180 | GEO

Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia

Project description:Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-RES-Luc+ (MOLM13 cells with a D835Y mutation generating a resistant phenotype) AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitor (gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 13 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and ATAC-seq was performed on HiSeq 4000, total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the chromatin accessibility changes induced by gilteritinib in MOLM13-RES AML xenograft model.

2021-07-07 | GSE179421 | GEO

Identifying molecular mechanisms of neural crest (NC) EMT and cell migration

Project description:Purpose: To identify differntially expressed transcripts in TP-0903 treated embryos that impair cranila NC EMT and cell migration in zebrafish embryos Methods: zebrafish embryos treated at 13 hpf with 5-7uM TP-0903 and DMSO for 1-, 4- and 8-hrs at 28Â°C. 35 embryos were collected for each treatment. Results: TP-0903 increases expression of several retinoic acid target genes including genes from within the retinoid pathway Conclusions: TP-0903 causes a direct increase in RA signaling that impairs cranial NC EMT and cell migration in zebrafihs embryos mRNA profiles of zebrafish embryos treated with TP-0903 and DMSO were generated by RNA-Seq, in quadruplicates, using Illumina Hi Seq

2016-02-18 | E-GEOD-72322 | biostudies-arrayexpress

Transcriptomic effects of combination Menin-MLL1 inhibition and FLT3 inhibition on human AML cells

Project description:Chromosomal translocations of the MLL1 gene cooccur with the activating mutations in FLT3 kinase in acute myeloid leukemia patients, providing the rationale to explore combination of the menin-MLL1 inhibitor (MI-3454) and FLT3 inhibitor (Gilteritinib) in leukemia models. Here, we pursued global gene expression studies after 7 days of treatment of MOLM13 cells (harboring MLL-AF9 and FLT3-ITD) with MI-3454 and Gilteritinib used as single agents and in combination. We observed that MYC, differentiation and stemness-associated gene programs were disrupted by the single agent treatments, but the effect was enhanced upon combinatorial treatment. These results provide a mechanistic input on the increased activity of MI-3454 when combined with Gilteritinib in leukemia models versus single agent treatment.

2020-12-17 | GSE149049 | GEO

Assessment of chromatin remodeling of acute myeloid leukemia cells treated with gilteritinib

Project description:Gilteritinib is a FLT3 inhibitor that has been approved for relapsed acute myeloid leukemia (AML) carrying FLT3 mutations. However, the effects of this drug on chromatin remodeling of AML cells remains unknown. We tested the state of chromatin openness of AML cells obtained from a patient before and after treatment with gilteritinib using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq).

2022-08-09 | GSE210617 | GEO

Identifying molecular mechanisms of neural crest (NC) EMT and cell migration

Project description:Purpose: To identify differntially expressed transcripts in TP-0903 treated embryos that impair cranila NC EMT and cell migration in zebrafish embryos Methods: zebrafish embryos treated at 13 hpf with 5-7uM TP-0903 and DMSO for 1-, 4- and 8-hrs at 28°C. 35 embryos were collected for each treatment. Results: TP-0903 increases expression of several retinoic acid target genes including genes from within the retinoid pathway Conclusions: TP-0903 causes a direct increase in RA signaling that impairs cranial NC EMT and cell migration in zebrafihs embryos

2016-02-18 | GSE72322 | GEO

BMX Kinase Mediates Gilteritinib Resistance in FLT3-mutated AML through Microenvironmental Factors

Project description:While clinical benefit has been observed with gilteritinib, most patients relapse through unknown mechanisms. To investigate mechanisms of gilteritinib resistance, we performed targeted genomic sequencing and single cell (sc) RNASeq on primary FLT3-ITD-mutated AML samples. Co-occurring mutations in RAS pathway genes were the most common. In gilteritinib-unresponsive patients, increased expression of bone marrow-derived hematopoietic cytokines and chemokines was observed after treatment compared to gilteritinib-sensitive patients. Expression of the TEK-family kinase, BMX, was higher in gilteritinib-unresponsive patients after treatment compared to gilteritinib-sensitive patients. BMX contributed to gilteritinib resistance in FLT3-mutant cells lines in a hypoxia-dependent manner by promoting pSTAT5 signaling, which was reversed with pharmacological inhibition and genetic knockout. In primary FLT3-mutated AML samples, pharmacological inhibition of BMX enhanced the antileukemic activity of gilteritinib and decreased chemokine expression. Gene module analysis associated gilteritinib responsiveness with lymphocyte differentiation and myeloid leukocyte activation. By contrast, unresponsiveness to gilteritinib associated with upregulation of cell-cycle, DNA/RNA metabolic processes, and protein translation. Together, these data support a role for microenvironment-mediated factors modulated by BMX in the escape from targeted therapy and gilteritinib resistance. This analysis provides a deeper understanding of targets and pathways for potential therapeutic intervention to restore gilteritinib sensitivity.

2022-07-07 | GSE199333 | GEO

Phosphoproteomic characterization of primary AML samples and relevance for response towards FLT3-inhibitors

Project description:Kinase hyperactivity is a common driver of acute myeloid leukemia (AML) and serves as a therapeutic target. The most frequent genetic aberration leading to hyperactive kinase signaling and poor prognosis is internal tandem duplication (ITD) of the FMS-tyrosine-like Kinase 3-gene (FLT3). FLT3-ITD induces ligand independent activation of FLT3 and downstream pathways leading to proliferation, decreased apoptosis and partial differentiation block. Combined with chemotherapy, FLT3-Tyrosine Kinase Inhibitor (FLT3-TKI) midostaurin improves overall survival (OS) of newly diagnosed FLT3-mutated AML patients, whereas single agent gilteritinib proved superior to chemotherapy in relapsed/refractory FLT3-mutated AML patients . As the primary targets of currently approved FLT3-TKIs are tyrosine (Y) kinases, we hypothesized that direct evaluation of tyrosine phosphorylation status could reveal pY phosphorylation profiles associated with FLT3-TKI response. Therefore, we used label-free pTyr-based phosphoproteomics in 35 primary AML samples (18 FLT3-WT, 17 FLT3-ITD), to identify differentially phosphorylated proteins underlying response to the FLT3-TKIs gilteritinib and midostaurin. We identified a total of 3024 unique phosphosites (median 1299 per sample, range 286 – 1612, pS:pT:pY 11.9%:9.5%:78.6%). Due to low number of identified phosphosites, we excluded two samples from further analyses. On the remaining 33 samples, we additionally performed IMAC global phosphoproteomics and on 17 samples protein expression analysis.

2021-09-10 | PXD024235 | Pride

shCDK9 or shDHODH sensitizes cells to gilteritinib treatment by altering transcriptomes of AML cells

Project description:Acquisition of an internal tandem duplication of the juxtamembrane region of FLT3 (FLT3-ITD) is a common event in Acute myeloid leukemia (AML) patients and is associated with poor outcomes at high allelic frequency. Although targeted therapies against FLT3-ITD exist, narrow therapeutic index as monotherapies and failure to achieve complete remission limits their clinical application. Using a genome-wide CRISPR knockout screen, we identified cyclin-dependent kinase (CDK9), protein arginine methyltransferase (PRMT5) and dihydroorotate dehydrogenase (DHODH) as novel synthetic lethal partners with gilteritinib treatment. We demonstrated that genetic or pharmacologic inhibition of these targets in combination with gilteritinib synergistically kill AML cells. The presence of FLT3-ITD was shown to cause a significant increase in aerobic glycolysis, rending the leukemia cells highly sensitive to pharmacological inhibition of glycolytic activity. Supportive of this, our screen shows that sgRNAs targeting ~28 genes in the glycolysis pathway are enriched in cells treated with gilteritinib, suggesting that switching to oxidative phosphorylation from aerobic glycolysis may represent a metabolic adaption of the leukemic cells to resistance to FLT3-targeted therapy. Interestingly, the knockdown of CDK9, PRMT5 or DHODH in presence of gilteritinib cooperatively shuts down oxidative phosphorylation and associated purine biosynthesis and mevalonate pathway, implying inhibition of these genes along with proteins involved in the mitochondria respiratory chain complexes and energy metabolism may represent an attractive strategy to resensitize leukemic cells to gilteritinib treatment. Overall, these findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and provide a rationale for a clinical trial of these novel combinatorial therapies.

2022-09-21 | GSE185519 | GEO

Phosphoproteomics of primary human FLT3-ITD+ AML cells treated with gilteritinib

Project description:Primary human AML cells (newly diagnosed, prior to treatment initation) were obtained from donor after consent and AML blasts were isolated by standard Ficoll centrifugation. AML blasts were treated with FLT3 inhibitor gilteritinib (or DMSO vehicle control) at 10 nM concentration for 6 h, followed by harvest for LC/MS.

2022-08-25 | PXD034080 | Pride

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